10-3781811-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 6P and 1B. PM1 PM2 PM5 BP4

The NM_001300.6(KLF6):c.506T>A(p.Leu169Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L169P) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KLF6 NM_001300.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.42

Genes affected

KLF6 (HGNC:2235): (KLF transcription factor 6) This gene encodes a member of the Kruppel-like family of transcription factors. The zinc finger protein is a transcriptional activator, and functions as a tumor suppressor. Multiple transcript variants encoding different isoforms have been found for this gene, some of which are implicated in carcinogenesis. [provided by RefSeq, May 2009]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a chain Krueppel-like factor 6 (size 282) in uniprot entity KLF6_HUMAN there are 5 pathogenic changes around while only 2 benign (71%) in NM_001300.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr10-3781811-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 7573.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.38323966).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KLF6	NM_001300.6	c.506T>A	p.Leu169Gln	missense_variant	2/4	ENST00000497571.6
KLF6	NM_001160124.2	c.506T>A	p.Leu169Gln	missense_variant	2/4
KLF6	NM_001160125.2	c.506T>A	p.Leu169Gln	missense_variant	2/3
KLF6	NR_027653.2	n.701T>A		non_coding_transcript_exon_variant	2/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KLF6	ENST00000497571.6	c.506T>A	p.Leu169Gln	missense_variant	2/4	1	NM_001300.6	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.0079	T
BayesDel_noAF	Benign	-0.25
Cadd	Benign	23
Dann	Uncertain	0.99
DEOGEN2	Benign	0.40	T;.;.
Eigen	Benign	0.17
Eigen_PC	Benign	0.050
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.68	T;T;T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.38	T;T;T
MetaSVM	Benign	-0.66	T
MutationAssessor	Pathogenic	3.0	M;M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-2.2	N;D;D
REVEL	Benign	0.15
Sift	Uncertain	0.0040	D;D;D
Sift4G	Uncertain	0.047	D;D;T
Polyphen		0.97	D;.;D
Vest4		0.53
MutPred		0.28		Loss of catalytic residue at L169 (P = 0.0761);Loss of catalytic residue at L169 (P = 0.0761);Loss of catalytic residue at L169 (P = 0.0761);
MVP		0.52
MPC		1.8
ClinPred		0.98	D
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.32
gMVP		0.62

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs121909143; hg19: chr10-3824003;